ABSTRACT Sudden cardiac arrest due to ventricular fibrillation (VF-SCA) is a major public health concern, and a leading cause of mortality in the US each year. Even in the setting of the best emergency medical systems, resuscitation efforts fail in most cases, with over 70% mortality. This application seeks to identify novel factors, erythrocyte membrane sphingomyelin and ceramide species, associated with 1) incidence of VF- SCA and 2) resuscitation outcomes following VF-SCA. Emerging evidence from cellular and animal experiments, and our previous work on membrane fatty acids and VF-SCA, lead us to these hypotheses: erythrocyte sphingomyelins and ceramides that contain the saturated fatty acid palmitic acid (16:0), are associated with higher risk of VF-SCA and a lower likelihood of resuscitation after VF-SCA; and erythrocyte sphingomyelins and ceramides that contain a saturated fatty acid with 20 carbons or more (20:0, 22:0 or 24:0), are associated with lower risk of VF-SCA and a greater likelihood of resuscitation. We take advantage of the Cardiac Arrest Blood Study Repository (CABS-R), a unique, ongoing, repository of data and specimens on SCA patients in King County, Washington, and optimized mass spectrometry methods to investigate the associations of erythrocyte membrane sphingomyelins and ceramides with the risk of incident VF-SCA (Aim 1) and with resuscitation outcomes following VF-SCA (Aim 2). To maximize the homogeneity of the SCA outcome, we will limit our investigation to SCA patients found in ventricular fibrillation by the attending paramedics. We will measure 8 primary (15 total) ceramide and sphingomyelin species in 4624 existing erythrocyte membrane samples, including 2312 from VF-SCA cases in CABS-R and 2312 from population controls, frequency- matched to cases on age, gender and calendar year. The investigation of VF-SCA risk (Aim 1) will be conducted in the 2312 VF-SCA cases from CABS-R and the 2312 population controls. For Aim 2, we will use outcome data on the VF-SCA cases from Aim 1 to investigate the associations of sphingomyelin and ceramide species with hospital admission, a proxy for cardiac resuscitation, and with discharge alive from the hospital, a proxy for brain resuscitation. The associations of these novel lipid species with both VF-SCA incidence and resuscitation outcomes will provide insight into biological pathways that influence the risk and outcomes of VF-SCA, inform potential novel prevention efforts and advance research involving treatment of VF-SCA.